Archives for: January 2007

Many pharmaceutical companies provide Continuing Medical Education (CME) for prescribing physicians. Although these programmes run by drug companies do not overtly market their drugs, physicians may get the impression that a disease or condition is underdiagnosed and best treated with a prescription. Following on from the previous column about the influence of pharmaceutical companies on medical research[1] there is now a resource listing ways for physicians to complete their CME credits without being influenced by the bias of drug companies.

The online resource, PharmedOut[2] is an independent project run by Georgetown University School of Medicine staff members for physicians and other prescribers:

"Our goal is to disseminate information about how pharmaceutical companies influence what we prescribe, to increase access to unbiased information about drugs, and to encourage physicians to choose pharma-free CME."

PharmedOut is one of more than 20 programmes funded by a $21 million grant from the Attorney General Consumer and Prescriber Grant Program[3] that are intended to teach physicians and nurses to more critically evaluate information from pharmaceutical companies about prescription drugs. Ironically the funding for the grant comes from a drug company, a settlement from a court case about unlawful marketing of a drug:

On May 13, 2004, Warner-Lambert, a division of Pfizer, Inc., entered into an Assurance of Voluntary Compliance/Discontinuance with the Attorneys General of 50 States and the District of Columbia to settle allegations that Warner-Lambert conducted an unlawful marketing campaign for the drug Neurontin® that violated state consumer protection laws. Among other things, the settlement provides for a $21 million Consumer and Prescriber Education grant program to be administered by a Special Committee of State Attorneys General pursuant to an Oregon Court Order and an Attorney General Memorandum of Understanding.

The grant will fund programs designed to provide health care professionals and consumers information relating to prescription drugs, including the way in which drugs are marketed.

Mini syllabi available on PharmedOut include:

* Your Friendly Drug Rep

* Why You Get Samples

* Industry Sponsored Research

* Disease Mongering

* Direct to Consumer (DTC) Promotion

Resources also include many links to other websites of similar organisations. The CME suggestions include the National Center for Complementary and Alternative Medicine (NCCAM) video lecture series,[4] along with many other options.

Pharmaceutical companies may be biasing the design of many large clinical trials to simply satisfy their own marketing needs rather than answering important clinical questions that may have a major influence on public health. According to an article in the New England Journal of Medicine (NEJM),[1] both outcomes would be desirable in an ideal world, and are not mutually exclusive.

The NEJM article comments on a study published in The Lancet,[2] the MEDAL programme, which compares the side-effects of two Cyclo-oxygenase-2 (COX-2) inhibitor non-steroidal anti-inflammatory drugs (NSAIDs): etoricoxib (Merck), and diclofenac (a 'well-tolerated' generic drug in use for over 30 years). This column has previously reported on the widely known association between COX-2 selective inhibitors and an increased risk of thrombotic cardiovascular events in placebo-controlled trials.[3] The Lancet study also compared the risk of gastro-intestinal complications (Inhibition of COX reduces prostaglandins in the lining of the stomach, making it more sensitive to corrosion by gastric secretions).

The Lancet study states:

"... no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac."

The conclusion of the study is:

"... rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs."

At first glance it may appear that the study usefully demonstrates the comparative cardiovascular risks of the traditional NSAID diclofenac, previously held to be well tolerated (but also a drug that is poisoning vultures in India [4]), while etoricoxib had a lower risk of gastrointestinal side-effects. The NEJM article however points out that the relative COX-2 selectivity of diclofenac is similar to that of celecoxib, and that the potential for increased cardiovascular risk with celecoxib may actually be higher than that of naproxen by 70% (naproxen is also a COX-2 inhibitor).[1] In addition, the Arthritis and Drug Safety and Risk Management Advisory Committees of the Food and Drug Administration recommended naproxen, not diclofenac, as the "preferred comparator" for large trials of COX-2 inhibitors.[1] So why was diclofenac the drug chosen for comparison? In an interview with the NEJM,[5] Dr. Robert Califf, vice chancellor for clinical research at Duke University said:

"The fact that the study did not use naproxen could be a signal that the investigators in the company were avoiding the comparison that had the highest probability of being adverse to what they were trying to achieve in the marketplace."

Dr. Califf suggests that if the study had been designed in a public forum it would "almost certainly" have used naproxen, and possibly a placebo, in which case it is unlikely that the company would spend hundreds of millions of dollars funding a study that would be likely to have adverse outcomes for their drug, but this is "probably about as good as it gets in the current system".

The NEJM article concludes:

"... the relative gastrointestinal safety of the two drugs remains unknown. Is the combination of naproxen and a proton-pump inhibitor as safe as or safer than etoricoxib for the gastrointestinal tract? ... the long tradition of leaving to the pharmaceutical industry the task of evaluating the efficacy and safety of its products has permitted manufacturers to make study-design choices that largely determine the shape of the answers eventually provided by the trials."

The incentive to attract pharmaceutical companies to invest in clinical trials designed by an independent unbiased process could be the perceived impartiality of such a process, which would encourage sponsors to evaluate their drugs in a manner that highlights their potential clinical value and not their anticipated marketing potential. If a non-commercially funded body were designing clinical trials such as the MEDAL programme, there are many natural medicines without severe adverse side-effects which could also have the chance of being compared with pharmaceutical medicines in addition to using a placebo,[6] and the results would probably be universally accepted rather than seen as simply adding to the plethora of biased pharmaceutical-funded drug trials.

The enzyme transglutaminase, which is added to some breads and croissants to make the dough more pliable, may act upon gliadin (a glycoprotein present in glutenous cereals) to generate the epitope associated with the coeliac response and with anaphylaxis to wheat.

A letter by two researchers in New Zealand published in the journal Trends in Food Science & Technology[1] suggests that transglutaminase (TG) should not be added to cereal products containing wheat, barley, rye or oats until safety checks have been carried out.

A researcher from the biochemistry laboratory in the Centre Hospitalier Chubert , Vannes in France later published an article in the journal Allergie et immunologie about the rôle of TG in both coeliac disease and wheat-dependent exercise-induced anaphylaxis (multi-system allergic reaction on exposure to wheat and during subsequent exercise).[2] The latter condition is not necessarily linked to gluten intolerance, but involves an IgE response.

Transglutaminases transform proteins by deamidation and/or transamidation, the latter cross-links proteins together. New epitopes have been suspected in cases of anaphylaxis to wheat isolates (a food ingredient consisting mainly of deamidated gluten proteins). As a microbial TG is included in many food technological processes, the author concludes: "its safe use should be checked. This assessment must cover not only the safety of the TG itself but also that of the deamidated/cross-linked proteins generated by this enzyme."

Diagnosis of wheat intolerance using skin prick testing and sensitization against wheat proteins is not very accurate.[3] As a result of this, the number of individuals diagnosed with irritable bowel syndrome (IBS) patients who have "food allergy" may be larger than believed.[4] If the interaction with the lectins in wheat germ agglutinin and blood group antigens is taken into account, a lot of the dietary intolerances to eating grain-based foods can be explained. Additives in factory-made baked goods is another reason to eat organically produced bread, with ingredients according to blood group.